SU988815A1 - Process for producing derivatives of delta-6-tetrahydro-1,2,4-triazinone-3 - Google Patents

Description

The invention relates to the synthesis of triazines, in particular, to the process for the preparation of 6-substituted and 2,6-disubstituted d-tetrahydro-1,2,4-triazinones-3 of the general formula, em where R. H, RC {, H5-V V BrCjH ,, which can be used as starting materials for the production of biologically active compounds and epoxy resins. . A known method for the preparation of 6-furyl substituted d-tetrahydro-l, 2,4-tri-azinone-3 involves the sequential acylation of α-amino-acetyl furan with chloroic acid ester, hydrazine of the carbamate intermediate and cyclization of the resulting hydrazone in an alkaline medium. The nitrosubstituted derivative of the obtained substance has a strong antimicrobial activity of C 13. The disadvantages of the method are the safety and long duration of the hydrazination stage (20 h). Closest to the invention is a method for producing 4-tetrahydro-1,2,4-triazinone-3 derivatives of the general formula CeHsjpf-R where R is H, consisting in recycling 5-feiyl-1, 3-9 Xazolinone-2 or 5 -phenyl-3-methyl-1 3-oxazyl-2-2 by working them with an excess of hydrazine hydrate when the reaction mass is boiled, followed by separation of the target products C2J. However, the yield of 6-substituted 4-tetrahydro-1,2,4-triazonon-3 derivatives, for example 6-phenyl D ° -tetrahydro-1, 2,4-triazinone-3, is not high according to this method (59%); At. The target product volume is not clean enough, which makes it difficult to isolate. In addition, the lack of reactivity of the original azolidone. for example, 5-phenyl-1, 3-oxazolino-2 does not allow to obtain 2 6-disubstituted derivatives of L -trahydro-1,2, 4 -triazinone-3 when treating the starting compounds, for example, phenylhydrazino b-alkyl derivatives of d6-tetrahydro-1,2,4-triazinone-3 are obtained. The disadvantage of this method is also the difficulty of synthesizing the starting materials, which are obtained in three stages from y-haloketone, for example, from chloroacetophenone, using current phosgene. The process for the preparation of the starting compounds involves the stages of the interaction of the Ch2 halogen ketone with ur tropine, followed by hydrolysis of ur tropine salt with hydrochloric acid and the formation of phenacylamine. In this case, the latter during the reaction is heavily contaminated with ammonium chloride, which makes it difficult to clean. Phenacilamine is then adhered and cyclized with phosgene. These deficiencies generally complicate the process technology. The purpose of the invention is to simplify the process technology. This goal is achieved by the fact that according to the method of obtaining derivatives and -tetrahydro-1,2,4-triazi-non-3 of the general formula iTf where R is H, CgH, R-, n is BrCfelij., CHg, as the initial derivatives of azolidones use (2,4-thiazolidinedionyl) -ketones of the general formula about lt-Shg.-to S (II) where R -, n - BgC (, H4. CHg, and the process is conducted in a medium of lower aliphatic alcohol or. Dioxane and / or water or an excess of phenylhydrazine. In the case of preparing 2,6-disubstituted derivatives of L-tetrahydro-1,2,4-triazinon-3 of general formula I, in order to increase the yield and purity of the target products, After the treatment of ketones of the general formula P with phenyl-gadrazine, it is necessary to isolate a mixture of direct intermediate E and Z-hydrazones of the ketones of the general formula P, treat it with trifluoroacetic acid when heated, followed by separation of the E-hydron and treat it with an alkali metal hydroxide when heated The process proceeds as follows:} -N-CHo-C-in IT I -No-SoS o 0 g -N-CHO-C-d pt IJ and 1 P I First, a mixture of isomeric and Z-hydrazones of Si is formed (2, If-thiazolidinedioNoyl) J -ketones. In the case of RH, recyclization occurs spontaneously, due to the low energy barrier of the transition of the Z-isomer to the E-isomer. In the case of R, the isomers become more stable and for their transformation either an acidic effect or a more rigid temperature regime is required when carrying out the reaction in an excess of phenylhydrazine without a solvent. In the latter case, the target 2, b-disubstituted derivatives of L ° -tetrahydro-1,2,4-triazinone-3 are obtained with a lower degree of purity and with a lower yield. Therefore, it is preferable to conduct the process with the release of intermediate E and Z-hydrazones and their transformation. The starting materials (2, C-thiazolidinedionyl)} - ketones I are obtained by reacting w-haloketones, for example, UJ-bromoketones, with 2,4-thiazolidinedione in the presence of bases in an alcohol-aqueous medium or with salts of 2,4-thiazolidinedione in the presence of quaternary salts ammonium in an inert solvent. The composition and structure of the synthesized compounds are confirmed by the data of elementary and functional analyzes, IR and PMR spectra, individuality - by thin-layer chromatography data. I мер Measure 1. b-Phenyl-L-tetragidro-l 2, 4-tripi-zinon-3. a) w-gm (2, 4-thiazolidinedione) 7-acetophenone. To a suspension of 11.7 g (0.1 mol) of 2,4-thiazolidinedione in 100 ml of methanol was added a solution of 5.6 g (0.1 mol) of potassium hydroxide in 30 mp of methanol, heated at 60 ° C for 10-15 minutes and distill off the solvent in vacuo to dry. To the resulting crystalline mass of the potassium salt of 2,4-thiazolidinedione, a solution of 19.9 g (0.1 mol) of IU-bromoacetophenone in 200 ml of chloroform was added and, with stirring, 1.65 g (0.01 mol) of tetraethylammonium chloride, Already at room temperature the exothermic reaction starts, the temperature of the reaction medium rises to 30-40 ° C. The resulting suspension is boiled for 1 h, cooled, the precipitate is filtered off. The filtrate is washed with TgieMH 50 ml portions of water and evaporated in vacuo to dry. Yield 22.1 g (.94%), m.p. 128-129 ° (from ethanol). R 0.88. Found,%: C 56.5; H 4.1, N 6.3, S 13.6; C-HgNOgS. Calculated,%: C 56.2; H 3.8; N 6.0; S 13.6. The same substance can be obtained by a different method. To a solution of 11.7 g (o, 1 mol) of 2,4-thiazolidinedione in 40 -ivui methano-, a solution of 5.6 g (0.1 mol of caustic potash in 60 ml of methanol is added, the mixture is cooled to 10-15 ° and to the resulting suspension of the potassium salt of 2,4-thiazolig dindione, 19.9 g of Co, 1 mol of U) -bromoacetophenone are added, stirred for 2-3 minutes and heated at 70-80 ° for 1 hour. Cooling, the precipitate is filtered off, washed with water, ether and dried. Yield 17.65 g (75%) m.p. 128-129 ° {from ethanol) R 0.88. It does not give a temperature depression by melting with a sample obtained by the described method. To a suspension of 4.7 g (0.02 mol) of the described yu- (2, -thiazolidinedione) -acetophenone in 20 ml of methanol was added 4 g (0.08 mol) hydrochloride / hydrochloride, the solution was boiled for 2 hours. cooled, the precipitate is filtered off, washed with ether, dried. Yield 2.55g. Another Q, 31 g was isolated from the filtrate. Total yield 2.86 g (82%), m.p. 231232 (from propanol). . Found,%: C 61.8; H 5.4; N 24, Calculated,%: C 61.7; H 5.1) N 24.0 In the sample, the displacement with the sample obtained according to the known method 2 does not give a depression and a melting point. IR spectrum (in dioxane) cm -; . o1724 (s), l) mn3320 (s), 3177 (ate). PMR spectrum (in dimethyl sulfoxide), m d: sLSN; 4.37 (C); , 36 (C); bmn. 10,07 (C). Example 2 6-p-Vromophenyl-D-tetrahydro-1; 2, 4-triazinon-3. w-fN- (2, V thiazolidinedione) 1-P-bromoacetophenone. Prepared analogously to example 1 of 5.85 (0.05 mol) of 2,4-thiazolidinedione, 2.8 g (0.05 mol) of potassium hydroxide and 13.9 g (0.05 mol) of AND-bromfenacil bromide in 50 ml methanol. The yield of 11.5 g (74%), so pl. 133-137 ° (from acetic acid). ftJ 0.88. Found,%: C 42.3; H 2.5; Br 25.5; N 4,5 S 10,0, - C HoBrNOaS. Calculated,%: C 42.0; H 2.5, "Br 25.4, - N 4.5, 510.2 6-p-Bromophenyl-L-tetrahydr6-1.2.4 triazinone-3 is prepared as in Example 1, 14 g (0.01 mol ) uj - {. N- (2, 4-thiazolidinedinyl) -n-bromoacetophenone and ±, g (0.03 mol / hydrazine hydrate in 6.5 ml of methanol. Yield 1.98 g (78%), so pl. --244-247 ° (from pro-, panol). R | 0.45. Found,%: C 42.7, And 3.0; Br 31.4, N 16.7; CgHgBrNaO., Calculated,% : C 42.5; H 3.2; Br 31.5ii N 16, -5 .. HJK-cneKTp (iB petroleum jelly, 1714 (s), 1700 (s), L / NH 3363 (ate) 3275 (cf. ), 3255 (cf.), 3160 (cf.), 3119 (cf.), 3087 (cf.),. NMR-spectrum (dimethyl sulfoxide, ppm, 4.34 (C), cf-NH 7.35 ( C), 10.09 (C). Example 3; 6 — Methyl-L-tetrahydro-1, 2,4-triazinon-Z. W (2, A — thiazolidinedione) 3-aceto To a suspension of 35.1 g (0.3 mol) of 2,4-thiazolidinedione in 20 ml of methanol, a solution of 16.8 g (0.3 mol) of potassium hydroxide in 90 ml of methanol is added, heated at 10-15 minutes and the solvent is distilled off in vacuum to dryness. To the obtained crystalline mass of 2,4-thiazolidinedione potassium salt is added a solution of 41.1 g (0.3 mol) of bromoacetone in 10 ml of chloroform and with stirring 1.65 g (7.5 mol) of tetraethylammonium chloride. Already at room temperature, an exothermic reaction starts, the temperature of the reaction medium rises to 30-40 °. Kip t I formed; the suspension is 2.5 hours, cooled, the precipitate is filtered off. The filtrate is evaporated in vacuo at 60 until complete separation. solvent and dried in vacuo at 100 ° for 10 min. The precipitate in the form of a dark brown, viscous mass is treated with 50 ml of ether, and triturated until complete crystallization of the product. The precipitate is filtered., Washed with ether, dried. The yield of 38.2 g (72%), so pl. 73-74 ° (from benzene with petroleum ether). RrO, 71. Found,%: C 42.0; H 4.1; N 8.2; S 18,4-, With HTNOjS. calculated%: C 41.6 H 4.1; N 8.1, S 18.5. To a solution of 2 g (0.02 mol of hydrazine hydrate in 1.2 ml, gradually add 1.73 g (0.01 mol) in portions with stirring. (N- (2, cythiazolidinedione)) acetone for 15 minutes. at room temperature, it is continued for 30 minutes. The resulting suspension is heated at 65-70 ° for 2 hours, cooled, the precipitate is filtered off, washed with ether, dried. The yield is 0.7 g (62%), mp. 156157 ° (from water ). R | 0.31. Found: C 42.6; H 6.3; N 37.6; C4H7MZO. Calculated,%: C 42.5; H 6.2, N 37.2. IR- spectrum (in vaseline oil), M-: Vc 0 1689 (s), VN-H 3430 (ate), 445 (. gel), 3244 (cf).

PMR spectrum (in dimethyl sulfoxide), m, d,: OL-CKg 3.72 (c), 6.83 (s), c Lmn 9.29 (s):

Example 4, 2,6-Diphenyl-tetrahydro-, 2, 4-triazinon-3.

B-Phenylhydrazone uj N- (2, -thiazolidinedione) -acetophenone.

JacTBOp 4.7 g (0.023 mol) of azolidone obtained (on the 5th according to Example 1, 25 ml (0.023 mol) of phenylhydrazine in 10 ml of 70% aqueous dioxane are boiled for 5 h. The suspension is cooled, the precipitate is filtered, washed with methanol , ether and dried, 4.75 (73%) isomeric mixtures of E and Z-hydrazones are obtained. Found: C 63.0; H 4.9; N 13.1; S 9.7; CH. Calculated,%: C 62.8; H 4.6; N 12.9; S 9.9.

The mixture is heated with 90 ml of trifluoroacetic acid at 78 ° C for 2 hours. At the same temperature, the solvent is distilled off. After cooling, the dark viscous mass is triturated with 1015 ml of water. The precipitate is filtered off, washed with methanol, and dried. Yield 4.45 g of a technical product that is purified, extracting impurities 47 ml of hot ethanol. The residue is dried. Yield 2.93 g (52%), m.p. 172174 (from ethanol), R | 0.83. It was found,%: C 63.2; H 5.0; N 12.8, -S 9.6; С И-, М OoS, Calculated,%: С 62.8; , H 4.6; I am 12.9; S 9.7.

To a suspension of 0.37 g (1.17 mol) of isolated E-hydrazone, c, b ml of 80% -Horo ethanol are added, 0.04 g (.2.34 mol) of caustic soda are added and boiled for 1.5 h. The newly formed suspension Rhlag is given, diluted 3-4 times with water, acetic acid is added to OH 7, the precipitate is filtered, washed with water, dried. Yield 0.28 g (95%), m.p. 224-22b ° (from ethanol). Found,%: C 72.2; H 5.6; N 16.9; C 5 N 73 No Oh. Calculated. %: C 71.8, H 5.2; N 16.7. ,

IR (dichloromethane), 1700 (C), VN-H 3440 (cf).

PMR spectrum (in dimethylsulfoxide, MD: s / C-Hz4.37 (c1 g), 7.62 (s).

This substance can be obtained in a one-step process.

A solution of 2.35 g (.0.01 mol) (2,1-thiazolidinedione) -acetophenone in 5.4 g (0.05 mol) of phenylhydrazine is heated at 105-110 ° 10 hours. Cool and mix with 200 ml of ether . The precipitate formed is filtered off, washed with ether and dried. The yield of the technical product is 1.05 g. After double recrystallization from propanol, 0.45 g (18%) of pure 2,6-diphenyl-dB-tetrahydro-1,2,4-triazinone-3 is obtained, mp 224-226 ° Does not depress the melting point. with a sample of the drug obtained by the above method.

Example 5, : -Phenyl-6-m-bromophenyl-D-tetrahydro-1, 2, 4-triazinon-3.

E-Phenylhydrazone (2, (- thiazolidinedione) J-p-bromoacetophenone, Solution 1.57 g (5 mmol) .azolidine, obtained in example 2, and Q, 56 g (5.2 mmol) of phenylhydrazine in 3 MP dioxane bale t 1.5 h, the solvent is distilled off in vacuum to 1/4

initial volume. The thick brown mass is washed with water until it partially solidifies, then triturated with a small amount of methanol to form a precipitate, filtered off, washed with 50% aqueous reagent, dried. 1.62 g (80%) of the isomeric mixture - and Z-hydrazones are obtained. Found,%: C 50.5; H 2.0; Br 19.6; N 10.4, S. 7.7; 0 s.

Calculated,%: C 50.5; H 2.2, Br 19.8, N 10.4; S 7.9.

The mixture is treated in the same manner as described in Example 4, 20 cd of trifluoroacetic a-acid. Output 0.84g

(52%), so pl. .163-165 ° (from ethanol). R | 0.84. Found,%: C 50.5; H 2.4; Br 19.6; N 10.5, 57.9; . Calculated,%: C 50.5 / H 2.2; Br 19.8; N 10.4 S 7.9.

2-Phenyl-6-P-bromophenyl-4-tetrahydro-1, 2,4-triazinon-3 is prepared, similarly to the triazinone described in example 4, from 0.58 g (1.44 mmol) of the obtained E-hydrazone and 0, 12 g

(2.88 mol) caustic soda in 6 ivin

80% ethanol. Output Oh ,, 42 g (89%) t,. Pl. 206-207 (from ethanol), Rr 0.68; Found: C 54.6; H 3.9, - Br 24.0, N 12.7; , 2VgMzO Calculated,%: C 54.5; H 3.6, Br 24.2, N 12.7. ,

IR spectrum (in dichloromethane), cm: Vtro 1702 (C), VN-H 3440 (cf). PMR spectrum (dimethyl sulfoxide),

MD: 1 (fl) (PMR spectra were taken at a spectrometer

Tes aBS-487C (80 MHz). The IR spectra were recorded on a VR-20 spectrometer, a layer thickness of 0.1–1 mm, a recording rate of 160 cm / min. Thin-layer chromatography is carried out in

standard conditions on alumina IY. Brockman degree of activity in methanol-chloroform (2: 1) (Rt) -, on Siluefol silica gel (in acetone-chloroform (4: 1) (R),

Benzene-acetone (1: 1) (R |), chloroformisopropanol (2: 1) (R), acetic acid - hexane - ethyl acetate (1: 1: 1) (R |).

The use of the proposed method in comparison with the known method provides a simplification of the process, concluding that the proposed starting materials for their synthesis II- N- (2, k-thiazolidinedione)} are ketones.

Claims (2)

and are more readily available and easily synthesized compounds. They are obtained from high yields directly from i-haloketones and 2,4-thiazolidinedione, which, in. A swap queue is obtained with the yield of 9i-U1e% of the path of interaction of thiourea and monochloroacetic acid. The method also provides a significant increase in yields of b-aryl-substituted 4-tetrahydro-1 2,4-triazinone-3. So, for 6-phenyl-4, tetrahydro-1, 2, 4-triazinone-3. the yield by the known method 2 J is 59% and by the sum of two herds 49%. According to the proposed method, these values are respectively 82 and 77, which increases the purity of the target products, due to the use of an organic solvent in the process. Thus, the melting point of 6-phenyl-l-tetrahydro-1,2,4-triazinone-3, obtained by fine method f2, wherein a large excess of hydrazine hydrate is used as the solvent, is 226-227 by the suggested method 231-232. The method provides obtaining new, not described in the literature, b-substituted and 2, b-disubstituted d-tetrahydro-1, 2, 4-triazinon-3, such as synthesized in examples 2-5 b -P-bromophenyl-L-tetrahydro-1 , 2,4-triazinon-3, b-methyl-L-tetraHydro-1, 2, 4-triazinon-3, 2, b-diphenyl-L-tetrahydro-1, 2, 4-triazinon-3, 2-phenyl b-p bromophenyl-d-tetrahydro-1, 2,4-triazinon-3. b-Alkyl and 2,6-disubstituted derivatives and -tetrahydro-1,2, 4-triazinone-3 could not be synthesized by a known method. Claim 1. Investigation of derivatives of D ° -tetrahydro-1,2,4-triazinone-3. to. General formula de N,. R - CfcHfi, p -, SND,. recycling azolidone derivatives by treating them with hydrazineide-. when heated, in order to simplify the process technology, (2,4-thiazolidinedionyl) ketones of the general formula o-Y-CH-CK H o Where R is CgHj, p is BcSbH4, CHj, 41 the process is carried out in an environment of lower aliphatic alcohol or dioxane and / or water or an excess of phenylhydrazine. 2. The method according to p. 1, about t l and h and -. so that, in order to increase the yield and purity of the target products, in the case of the preparation of 2,6-disubstituted derivatives of D-tetrahydro-1, 2,4-triazinone-3 of general formula T, after treatment with ketoes of general formula 11 phenylhydrazine is isolated a mixture of intermediate E and Z-hydrazones of ketones of the general formula I, it is treated with trifluoroacetic acid when heated, followed by release of E-hydrazone and its treatment with an aqueous-alcoholic solution of an alkali metal hydroxide during acidification. Sources of information, drawn into consideration in the examination 1. US patent number 3138593, cl. 260-648, publ. 1964. 2. USSR author's certificate number 256777, cl. C 07 D 253/06, 1968 (prototype).